The present invention pertains generally to modulation of activation of the complement system. More particularly, the present invention pertains to the inhibition of complement activation through the inhibition of platelet receptors for thrombin/fibrinogen. In a preferred embodiment, the present invention pertains to a method of inhibiting of transplant rejection by blocking complement activation in a recipient.
The complement system is a complex interaction of plasma proteins and membrane cofactors which act in a multi-step, multi-protein cascade sequence in conjunction with other immunological systems of the body to provide immunity from intrusion of foreign cells. Complement proteins represent up to about 10% of globulins in normal serum of man and other vertebrate""s. The term xe2x80x9ccomplementxe2x80x9d refers to the non-specific defense system that is activated by the bonding of antibodies to antigens and by this event is directed against specific invaders that have been identified by antibodies.
Organ procurement currently poses one of the major problems in organ transplantation, as the number of patients requiring transplants far exceeds the number of organs available. Moreover, a transplanted organ is often rejected by the recipient""s body. Thus, even when an organ is available, transplant rejection presents a continuing problem.
Xenotransplantation may provide a solution to the shortage of organs for transplant. Phylogenetically, non-human primates are the most closely related species to humans and might therefore represent the first choice as donors. In 1969, Reetsma et al. achieved the first successful kidney human xenograft from a chimpanzee (Reetsma, K., et al., 1964, Ann. Surg. 160:384). However, the potential utilization of primate donors is limited by insufficient numbers, legal and ethical considerations, and the potential for transmitting dangerous viral diseases. Swine represent one of the few large animal species in which breeding characteristics make genetic experiments possible, making it possible to develop MHC homozygous lines of miniature swine, for example. Miniature swine can be maintained at maximum adult weights of 200 to 300 lbs and are anatomically and physiologically close to humans. Therefore, the organs of miniature swine seem appropriate for use as xenografts for human beings of all ages.
However, problems associated with transplant rejection also persist with respect to xenograft organs from swine and from other donors. Therefore, there remains a continuing and long-felt need for therapeutic methods that inhibit transplant rejection and that faciliate the use of xenograftt organs in transplant procedures.
A method of modulating complement activation in a warm-blooded vertebrate is disclosed. The method comprises administering a therapeutically effective amount of a platelet activity modulator to a warm-blooded vertebrate, whereby complement activation is modulated. The platelet activity modulator preferably comprises a combination of a GPIb modulator and a GPIIb/GPIIIa modulator.
A method of inhibiting complement activation by a transplanted tissue in a warm-blooded vertebrate is also disclosed. The method comprises administering a therapeutically effective amount of a platelet activity modulator to a warm-blooded vertebrate before, during or after a tissue is transplanted to the warm-blooded vertebrate, whereby complement activation, by the transplanted tissue is inhibited. The platelet activity modulator preferably comprises a combination of a GPIb modulator and a GPIIb/GPIIIa modulator.
The therapeutically effective amount of the platelet activity modulator ranges from about 0.01 mg to about 10,000 mg per day, preferably from about 0.1 mg to about 1,000 mg per day, and more preferably from about 1 mg to about 300 mg per day.
The transplanted tissue can be a vascularized tissue. The vascularized tissue can include, but is not limited to heart, lung, liver, kidney, pancreas and combinations thereof.
The transplanted tissue can be xenograft tissue. The xenograft tissue can be vascularized xenograft tissue. The vascularized xenograft tissue can include, but is not limited to, heart, lung, liver, kidney, pancreas and combinations thereof. Optionally, the xenograft tissue is obtained from a donor animal having a deficient platelet activity pathway.
A method of inhibiting rejection of a transplanted tissue in a warm-blooded vertebrate is also disclosed. The method comprises administering a therapeutically effective amount of a GPIb modulator and a GPIIb/GPIIIa modulator to a warm-blooded vertebrate before, during or after a tissue is transplanted to the warm-blooded vertebrate, whereby rejection of the transplanted tissue is inhibited.
A method of enhancing tolerance of a xenograft transplant in a recipient is also disclosed. The method comprises administering a therapeutically effective amount of a GPIb modulator and a GPIIb/GPIIIa modulator to a recipient before, during or after the recipient receives a xenograft transplant, whereby tolerance of the xenograft transplant is enhanced.
Accordingly, it is an object of the present invention to provide a novel method for inhibiting transplant rejection. This and other objects are achieved in whole or in part by the present invention.
An object of the invention having been stated hereinabove, other objects will become evident as the description proceeds when taken in connection with the accompanying Drawings and Laboratory Examples as best described hereinbelow.